T cell epitope clustering in the highly immunogenic BZLF1 antigen of Epstein-Barr virus

Polymorphism in the human leukocyte antigen (HLA) loci ensures that the CD8 T cell response to viruses is directed against a diverse range of antigenic epitopes, thereby minimizing the impact of virus escape mutation across the population. The BZLF1 antigen of Epstein-Barr virus is an immunodominant target for CD8 T cells, but the response has been characterized only in the context of a limited number of HLA molecules due to incomplete epitope mapping. We have now greatly expanded the number of defined CD8 T cell epitopes from BZLF1, allowing the response to be evaluated in a much larger proportion of the population. Some regions of the antigen fail to be recognized by CD8 T cells, while others include clusters of overlapping epitopes presented by different HLA molecules. These highly immunogenic regions of BZLF1 include polymorphic sequences, such that up to four overlapping epitopes are impacted by a single amino acid variation common in different regions of the world. This focusing of the immune response to limited regions of the viral protein could be due to sequence similarity to human proteins creating "immune blind spots" through self-tolerance. This study significantly enhances the understanding of the immune response to BZLF1, and the precisely mapped T cell epitopes may be directly exploited in vaccine development and adoptive immunotherapy

GRB 060313: A New Paradigm for Short-Hard Bursts?

We report the simultaneous observations of the prompt emission in the gamma-ray and hard X-ray bands by the Swift-BAT and the KONUS-Wind instruments of the short-hard burst, GRB 060313. The observations reveal multiple peaks in both the gamma-ray and hard X-ray bands suggesting a highly variable outflow from the central explosion. We also describe the early-time observations of the X-ray and UV/Optical afterglows by the Swift XRT and UVOT instruments. The combination of the X-ray and UV/Optical observations provide the most comprehensive lightcurves to date of a short-hard burst at such an early epoch. The afterglows exhibit complex structure with different decay indices and flaring. This behavior can be explained by the combination of a structured jet, radiative loss of energy, and decreasing microphysics parameters occurring in a circum-burst medium with densities varying by a factor of approximately two on a length scale of 10^17 cm. These density variations are normally associated with the environment of a massive star and inhomogeneities in its windy medium. However, the mean density of the observed medium (n approximately 10^−4 cm^3) is much less than that expected for a massive star. Although the collapse of a massive star as the origin of GRB 060313 is unlikely, the merger of a compact binary also poses problems for explaining the behavior of this burst. Two possible suggestions for explaining this scenario are: some short bursts may arise from a mechanism that does not invoke the conventional compact binary model, or soft late-time central engine activity is producing UV/optical but no X-ray flaring.Comment: 28 pages, 6 figures. Accepted for publication in ApJ. Clarifications made and typos correcte

CD8+ T-cell specificity is compromised at a defined MHCI/CD8 affinity threshold

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity

CD8+ T-­cell specificity is compromised at a defined major histocompatibility complex class I/CD8 affinity threshold

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity

Living on a flammable planet: interdisciplinary, cross-scalar and varied cultural lessons, prospects and challenges: Table 1.

Living with fire is a challenge for human communities because they are influenced by socio-economic, political, ecological and climatic processes at various spatial and temporal scales. Over the course of 2 days, the authors discussed how communities could live with fire challenges at local, national and transnational scales. Exploiting our diverse, international and interdisciplinary expertise, we outline generalizable properties of fire-adaptive communities in varied settings where cultural knowledge of fire is rich and diverse. At the national scale, we discussed policy and management challenges for countries that have diminishing fire knowledge, but for whom global climate change will bring new fire problems. Finally, we assessed major fire challenges that transcend national political boundaries, including the health burden of smoke plumes and the climate consequences of wildfires. It is clear that to best address the broad range of fire problems, a holistic wildfire scholarship must develop common agreement in working terms and build across disciplines. We must also communicate our understanding of fire and its importance to the media, politicians and the general public. This article is part of the themed issue ‘The interaction of fire and mankind’

The Wide-field Infrared Survey Explorer (WISE): Mission Description and Initial On-orbit Performance

The all sky surveys done by the Palomar Observatory Schmidt, the European Southern Observatory Schmidt, and the United Kingdom Schmidt, the InfraRed Astronomical Satellite and the 2 Micron All Sky Survey have proven to be extremely useful tools for astronomy with value that lasts for decades. The Wide-field Infrared Survey Explorer is mapping the whole sky following its launch on 14 December 2009. WISE began surveying the sky on 14 Jan 2010 and completed its first full coverage of the sky on July 17. The survey will continue to cover the sky a second time until the cryogen is exhausted (anticipated in November 2010). WISE is achieving 5 sigma point source sensitivities better than 0.08, 0.11, 1 and 6 mJy in unconfused regions on the ecliptic in bands centered at wavelengths of 3.4, 4.6, 12 and 22 microns. Sensitivity improves toward the ecliptic poles due to denser coverage and lower zodiacal background. The angular resolution is 6.1, 6.4, 6.5 and 12.0 arc-seconds at 3.4, 4.6, 12 and 22 microns, and the astrometric precision for high SNR sources is better than 0.15 arc-seconds.Comment: 22 pages with 19 included figures. Updated to better match the accepted version in the A

Identification of human viral protein-derived ligands recognized by individual MHCI-restricted T-cell receptors

Evidence indicates that autoimmunity can be triggered by virus-specific CD8+ T cells that crossreact with self-derived peptide epitopes presented on the cell surface by major histocompatibility complex class I (MHCI) molecules. Identification of the associated viral pathogens is challenging because individual T-cell receptors can potentially recognize up to a million different peptides. Here, we generate peptide length-matched combinatorial peptide library (CPL) scan data for a panel of virus-specific CD8+ T-cell clones spanning different restriction elements and a range of epitope lengths. CPL scan data drove a protein database search limited to viruses that infect humans. Peptide sequences were ranked in order of likelihood of recognition. For all anti-viral CD8+ T-cell clones examined in this study, the index peptide was either the top-ranked sequence or ranked as one of the most likely sequences to be recognized. Thus, we demonstrate that anti-viral CD8+ T-cell clones are highly focused on their index peptide sequence and that ‘CPL-driven database searching’ can be used to identify the inciting virus-derived epitope for a given CD8+ T-cell clone. Moreover, to augment access to CPL-driven database searching, we have created a publicly accessible webtool. Application of these methodologies in the clinical setting may clarify the role of viral pathogens in the etiology of autoimmune diseases

Allelic polymorphism in the T cell receptor and its impact on immune responses

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01 public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501 revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection

Sport and physical activity in the lives of looked-after children: a ‘hidden group’ in research, policy and practice

Looked-after children are arguably one of the most disadvantaged groups in society and constitute a ‘hidden group’ in relation to sport and physical activity research, policy and practice. Research on looked-after children has explored the views of caregivers, practitioners and policy-makers who have often been asked to speak for children on their behalf. Through the use of the mosaic approach and innovative participatory methods, including peer interviewing, the purpose of this paper was to provide an insight into a new area of research in the field of sport and physical activity. As such, it reports on initial findings from a wider project with looked-after children that explores their sport and physical activity experiences. Specifically, it asks the following: (1) What are the sport and physical activity experiences of looked-after children? (2) What meanings and values do looked-after children ascribe to their engagement in sport and physical activity? Findings from the voices of four male looked-after children highlight that these young people used sport as a means to an end; to spend time with friends and develop stocks of social capital. However, due to changes in placement, they also experienced disrupted patterns of engagement coupled with additional institutional constraints that shaped access to sporting activities